Gene targeting in mouse embryonic stem cells is a powerful technique that has revolutionized biomedical research in the last 10 years. In gene targeting, specific mutations are introduced into any gene of interest. These mutations can be complete deletions, or defined and limited changes in the amino acid sequence or even the regulatory elements of the gene in question. Once the mutation has been introduced into the embryonic stem (ES) cells in culture, these ES-cells are then injected into normal mouse blastocysts. The injected blastocyst is then implanted into the uterus and allowed to develop to term. The resulting pups are chimeras or mosaics, as they contain cells derived from the host blastocyst as well as the mutated ES-cells. Often the ES-cells contribute to the germ line of the chimera, which then allows for the recovery of the mutated allele in the offspring of the chimera. Finally, the resulting heterozygous mice can be bred to homozygocity and the phenotype can be analyzed. During the course of the last five years the focus of the Program Project has changed in such a way that now all five projects involve gene targeting. An effective way to perform the labor-intensive and technically demanding ES-cell culture would be through the establishment of an ES-cell Core, which would then serve the gene targeting needs of all five labs involved in the program project. This is also more cost-effective then setting up ES-cell culture facilities in all five laboratories. In addition to the anticipated technical benefits of the Core, the ES Core will be a focal point for dissemination of information about mouse reagents and lines that are available. This, in turn, will lead to future collaborations and interactions beyond what is proposed at the present time.